Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proliferative rate as well as the activity of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase, which regulates de novo synthesis of mevalonate, was comparable in the two human breast cancer cell lines Hs578T and MDA-231 when cultured in the presence of serum. Upon treatment with mevinolin (an HMG CoA reductase inhibitor) the proliferation of the cell lines was depressed with similar dose response kinetics. A depression of the enzymatic activity to a level of 1-1.5 pmol mevalonate/min/mg protein decreased DNA-synthesis by approximately 90%. In contrast, at slightly higher enzymatic activities, ie 2-2.5 pmol/min/mg protein, there was only a mild decrease in DNA-synthesis. Addition of mevalonate to a final concentrations of 0.77 mM completely prevented the mevinolin-induced block on cell proliferation in both cell lines. Exposure to serum-free medium caused by itself a depression of HMG CoA reductase activity to 2.5-3 pmol/min/mg protein in both cell lines. Whereas the proliferation of MDA-231 was not inhibited at all by serum depletion, this treatment decreased DNA-synthesis in Hs578T by nearly 80%. Interestingly, the addition of mevalonate also prevented this growth inhibition in Hs578T, irrespective of whether mevinolin was present or not. However, this required a 30-fold increase in the mevalonate concentration (23.1 mM) as compared to MDA-231. The present data indicate that mevalonate is not only necessary for cell proliferation, but also that mevalonate is involved in the serum-dependent control of cell proliferation in serum-sensitive cells. In this respect, serum seems to affect the utilization of mevalonate in the formation of mevalonate-derived growth-regulatory molecules, rather than regulating the de novo synthesis of mevalonate.
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PMID:Requirement for mevalonate in the control of proliferation of human breast cancer cells. 158 May 50

Synchronization of mammalian cells is essential for investigations involving cell proliferation. A simple method for obtaining synchrony in all types of cells, through several cycles and with minimal overall metabolic perturbations, has not yet been available. We describe a procedure for synchronizing normal as well as tumor cells reversibly in the G1 phase of the cell cycle using Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. This method of synchronization was successful with all cell lines tested, including normal and tumor cells of mouse, hamster, and human origins. For example, when MCF-7 human breast cancer cells were synchronized with Lovastatin and released by the addition of mevalonic acid (the product of the reaction catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase), 3 phases of accelerated thymidine incorporation into DNA corresponding to 3 S phases of the cell cycle occurred during a 90-h period of cell replication. Thymidine incorporation was decreased to less than or equal to 4% during the initial lag of 18 h before the first S phase, and maximum incorporation was then achieved after only 6 h. The antibody Ki-67, which detects a nuclear antigen associated with proliferation, was present in cells arrested with Lovastatin. This fact, together with the lack of thymidine incorporation during the initial lag time, indicates that the cells were arrested in the G1 and not in the G0 phase of the cell cycle. Furthermore, in synchronized tumor-derived human breast epithelial cells, histone H4 RNA was low after Lovastatin release and increased with the onset of DNA synthesis. Concomitant synthesis of DNA and histone H4 RNA expression could be observed for 2 cycles. Minimal perturbations of general metabolic functions occurred since the rate of RNA, protein, and initial DNA synthesis were unaffected by Lovastatin, as evidenced by [3H]uridine, [3H]leucine, and initial [3H]thymidine incorporation. Finally, while the Lovastatin-induced synchronization was overcome by mevalonic acid, addition of squalene or cholesterol-ethanol had no such effect. Thus, Lovastatin appears to prevent formation of an early intermediate in the cholesterol pathway that is essential for progression of cells through early G1 phase.
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PMID:Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. 171 13

The relationship between the effects of EGF and mevalonate on proliferation of the breast cancer cell line Hs578T was investigated. When Hs578T cells were depleted of serum their proliferation was drastically retarded. This was partially counteracted by insulin or IGF-1 but not by EGF. However, if the activity of HMG-CoA reductase was inhibited, there was a significant increase in DNA synthesis of EGF-treated cells. This effect was not seen in cells stimulated by insulin or IGF-1, and was prevented by addition of mevalonate. The results suggest that mevalonate, or some of its products, inhibits steps in the EGF signal pathway.
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PMID:Inhibitory effect of mevalonate on the EGF mitogenic signaling pathway in human breast cancer cells in culture. 772 40

The possible growth regulatory role of isoprenoids (mevalonate-derived products) in secondary cultures of normal human mammary epithelial cells (HMEC), as compared to the two human breast cancer cell lines Hs578T and MDA231, was investigated. All three cell types responded promptly to inhibitors of HMG CoA reductase and thereby became arrested. Whereas the growth of MDA231 cells was totally independent of exogenous growth factors, the proliferation of HMEC and Hs578T was blocked or partially blocked, respectively, following growth factor-depletion. Closer analysis showed that the depressive effects on cell growth, induced by HMG CoA reductase inhibition and growth factor depletion, were from a kinetic point of view identical. These data suggest that the biosynthesis of isoprenoids may comprise one event involved in the intracellular mechanisms lying behind the growth factor-mediated growth of mammary epithelial cells. The effects of addition of different known isoprenoids on growth of cells subjected to HMG CoA reductase inhibition or growth factor depletion were also investigated. It was found that coenzyme Q and dolichol significantly delayed growth arrest in all three cell types. In contrast, cholesterol and isopentenyladenine were ineffective.
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PMID:Effects of isoprenoids on growth of normal human mammary epithelial cells and breast cancer cells in vitro. 816 38

Proliferation of exponentially growing breast cancer cells (line Hs578T) was blocked specifically in G1 by 3-hydroxy-3-methylglutaryl Coenzyme A (HMG CoA) reductase inhibition, as well as by inhibition of N-linked glycosylation. As a consequence of these inhibitory conditions, the cells were synchronized in the G1 stage of the cell cycle. The similarities in the kinetic responses point to the possibility that the two different types of metabolic inhibitions block cell cycle progression by common mechanisms. One possibility is that the inhibition of HMG CoA reductase activity also leads to a depressed rate of N-linked glycosylation, which in turn may constitute the critical event for cell cycle progression and cell growth. In order to investigate whether this relationship exists in breast cancer cells, cells synchronized in G1 by mevinolin (an inhibitor of HMG CoA reductase) were used. Upon addition of mevalonate, whose endogenous synthesis is catalysed by HMG CoA reductase, the cells entered S phase after a 4 h pre-replicative period. Mevalonate stimulation also led to a rapid and substantial increase in N-linked glycosylation, measured by determining the uptake of radioactive glucosamine. This metabolic event was found to be of critical importance for the initiation of DNA synthesis. However, as soon as the cells had entered S phase, they were independent of the level of N-linked glycosylation.
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PMID:Cell cycle-specific growth inhibition of human breast cancer cells induced by metabolic inhibitors. 828 60

Treatment with 25-hydroxycholesterol, an inhibitor of HMG CoA reductase activity, efficiently blocked the proliferation of both human normal mammary epithelial cells (HMEC) and breast cancer cells (MDA231). Upon release of the block there was a rapid increase in the HMG CoA reductase activity, which reached a maximum 4 h after removal of the inhibitor, in both cell types. In MDA231 this increase in enzymatic activity was followed by a rapid initiation of DNA synthesis, whereas this process started considerably later in HMEC. Even in HMEC stimulated to DNA synthesis by insulin, there was first an increase in HMG CoA reductase activity with a maximum 4 h after the addition of the mitogen. If 25-hydroxycholesterol was added along with insulin, the subsequent initiation of DNA synthesis was prevented. Following a 25-hydroxycholesterol treatment as short as 4 h, the onset of DNA synthesis was delayed, indicating that a certain level of HMG CoA reductase activity (= mevalonate synthesis) in the early and mid stage of the prereplicative phase is required for the transduction of the signal leading to initiation of DNA synthesis. In concurrence with these data, it was also demonstrated that giving an exogenous supply of mevalonate to the insulin-stimulated HMEC results in a faster initiation of DNA synthesis.
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PMID:Regulatory role of mevalonate in the growth of normal and neoplastic human mammary epithelial cells. 835 28

HMG-CoA reductase inhibitors, such as Lovastatin and Simvastatin, cause cell cycle arrest by interfering with the mitogenic activity of mitogens present in culture media. Cells are induced to pause in G1 and can readily resume growth upon removal of the enzymatic block. Estrogens, acting via their nuclear receptor, are mitogens for different normal and transformed cell types, where they foster cell cycle progression and cell division. In estrogen-responsive MCF-7 human breast cancer cells, but not in non responsive cells, 17 beta-estradiol (E2) induces cells arrested with Lovastatin or Simvastatin to proliferate in the presence of inhibitor, without restoring HMG-CoA reductase activity or affecting the protein prenylation pattern. Mitogenic stimulation of G1-arrested MCF-7 cells with E2 includes primary transcriptional activation of c-fos, accompanied by transient binding in vivo of the estrogen receptor and/or other factors to the ERE and the estrogen-responsive DNA region of this proto-oncogene, as detected by dimethylsulphate genomic footprinting analysis. Mitogenic stimulation of growth-arrested MCF-7 cells by E2 occurs, under these conditions, without evident activation of ERK-1 and -2 kinases, and thus independently from the mitogen-responsive signal transduction pathways that converge on these enzymes.
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PMID:17 beta-Estradiol overcomes a G1 block induced by HMG-CoA reductase inhibitors and fosters cell cycle progression without inducing ERK-1 and -2 MAP kinases activation. 863 97

MCF-7 human breast cancer cells express functional estrogen receptor and grow in response to estrogen stimulation. G(1)-synchronized MCF-7 cells, made quiescent by exposure to the HMG-CoA reductase inhibitor Simvastatin in estrogen-free medium, readily resume cell cycle progression upon stimulation with 17beta-estradiol (E(2)), even under conditions where polypeptide growth factor-triggered signal transduction pathways are inhibited by the continuous presence of Simvastatin in the culture medium. Under these conditions, cyclin D(1) gene transcription is transiently induced within the first 1-9 h of stimulation, as shown by the accumulation of cyclin D(1) mRNA and protein (p36(D(1))) in the cell and by enhanced expression of stably transfected D(1) promoter-luciferase hybrid genes. Estrogen-induced p36(D(1)) associates readily with p32(cdk2) and p34(cdk4), but not with p31(cdk5), which is however abundantly expressed in these cells. Only p36(D(1))-p34(cdk4) complexes are activated by E(2), as detected in cell extracts by immunoprecipitation with anti-D(1) antibodies followed by assessment of phosphotransferase activity toward the retinoblastoma (Rb) gene product and by analysis of p105(Rb) phosphorylation in vivo. An estrogen-responsive regulatory region has been mapped within the first 944 bp upstream of the transcriptional startsite of the human D(1) gene. Sequence analysis of this DNA region reveals that the cis-acting elements responsive to estrogen are likely to be different in this case from the canonical EREs.
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PMID:17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells. 864 71

The metabolism of 25-hydroxycholesterol in different cell types was studied and the role of 7 alpha-hydroxylation for the effect of 25-hydroxycholesterol on the activity of HMG-CoA reductase was determined. Human diploid fibroblasts (HDF) and the human melanoma cell line SK-MEL-2 converted 25-hydroxycholesterol into 7 alpha,25-dihydroxycholesterol and 7 alpha,25-dihydroxy-4-cholesten-3-one while the virus-transformed fibroblast line 90VA-VI, the colon carcinoma cell line WiDr and the breast cancer cell line MDA-231 did not express 7 alpha-hydroxylase activity. The 7 alpha-hydroxylation of 25-hydroxycholesterol in HDF could be stimulated by dexamethasone and cortisol and inhibited by metyrapone. An unidentified, possibly 4-hydroxylated, metabolite was formed by 90VA-VI cells and a polar, probably conjugated, metabolite was formed by WiDr cells. The 7 alpha-hydroxylated metabolites of 25-hydroxycholesterol suppressed the activity of HMG-CoA reductase to a similar extent as 25-hydroxycholesterol in HDF but not in 90VA-VI cells, while the 7 alpha-hydroxylated metabolites of 27-hydroxycholesterol suppressed the activity of HMG-CoA reductase also in 90VA-VI cells. The suppression of HMG-CoA reductase activity by 25- and 27-hydroxycholesterol was decreased or abolished by dehydroepiandrosterone or pregnenolone which have little or no effect on the 7 alpha-hydroxylation. The results indicate that 7 alpha-hydroxylation is not directly involved, positively or negatively, in the action of 25- or 27-hydroxycholesterol as suppressors of HMG-CoA reductase activity.
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PMID:Studies on the relationships between 7 alpha-hydroxylation and the ability of 25- and 27-hydroxycholesterol to suppress the activity of HMG-CoA reductase. 905 14

It is well established that dietary n-6 polyunsaturated fatty acids (PU-FAs) enhance rat mammary tumor development whereas n-3 PUFAs inhibit it, yet the mechanisms are unclear. The objective of this study was to investigate a mechanism by which n-3 and n-6 PUFAs could modulate mammary carcinogenesis. Female Sprague Dawley rats were fed diets containing either menhaden (n-3) or safflower oil (n-6) in a 7% fat diet for 1 week. In comparison to the n-6 diet, the n-3 diet significantly reduced the activity and levels of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase in mammary glands, thereby suppressing the formation of mevalonate. In addition to being essential for cholesterol biosynthesis, mevalonate is also required for DNA synthesis and may be involved in malignant transformation. Serum cholesterol was lower in the n-3 group than in the n-6 group (1.91 +/- 0.18 versus 2.61 +/- 0.37 mM; P < 0.01). Extrahepatic tissues meet most of their cholesterol requirements from circulating cholesterol, and the internalized cholesterol down-regulates HMG-CoA reductase. Thus, the concomitant decrease in serum cholesterol and mammary gland HMG-CoA reductase levels suggests that changes in circulating cholesterol levels do not solely determine the activity of extrahepatic reductase. We conclude that the mevalonate pathway may be a mechanism through which different types of dietary fat modulate breast cancer development.
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PMID:Regulation of mevalonate synthesis in rat mammary glands by dietary n-3 and n-6 polyunsaturated fatty acids. 928 73


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